Abstract The goal of this project is to develop an optimized MNK inhibitor for neuropathic pain treatment. MNK is a kinase that phosphorylates eIF4E to control the translation of a distinct subset of mRNAs. Our focus on this target for neuropathic pain is grounded in evidence that MNK-eIF4E signaling is activated in nociceptors upon exposure to pain promoting cytokines and growth factors as well as by peripheral nerve injury, all of which are common factors tied to intractable neuropathic pain. Importantly, activation of this pathway in nociceptors increases their excitability, and genetic or pharmacological inhibition of MNK signaling blocks and reverses this hyperexcitability as well as behavioral signs of neuropathic pain. Critically, treatment of dorsal root ganglion (DRG) neurons taken from people with neuropathic pain with MNK inhibitors leads to reversal of nociceptor spontaneous activity, which is thought to be a key driver of neuropathic pain in patients. MNK inhibitors have been described, but a particular class of molecules, of which eFT508 (a clinical phase drug for cancer) is the prototype, show strong specificity for MNK. This molecule will be our starting point for optimization of a new molecule for the treatment of neuropathic pain. eFT508 requires optimization because MNK inhibition in the central nervous system (CNS) may lead to depression, an unacceptable side effect for a neuropathic pain drug. Our group, 4E Therapeutics, plans a targeted medicinal chemistry and screening campaign directed at generating a MNK-inhibitor-based neuropathic pain treatment with the goal of restricting its central nervous system (CNS) penetration while retaining potency, specificity and in vivo bioavailability and efficacy. In PHASE ONE of this project compounds will be synthesized and screened against human MNK1 and 2 to assess potency and then will undergo in vitro ADM and pharmacokinetic (PK) studies in rats to assess plasma to brain drug concentrations. Compounds that have favorable peripheral PK but lack blood brain barrier (BBB) penetration will then be tested for in vivo efficacy in neuropathic pain models in rats and compared directly to eFT508. PHASE TWO will focus on human DRG efficacy and toxicology studies to verify choice of lead clinical candidate and backup compounds culminating with an IND-enabled MNK1/2 inhibitor optimized for peripheral neuropathic pain treatment.